DESCRIPTION: (Adapted from the applicant's abstract and Specific Aims.) Qualitative and quantitative defects of lung surfactant are important in both membrane disease and the adult respiratory distress syndrome (ARDS). Surfactant specific proteins are required for normal surfactant function and metabolism but their physiologic roles and the primary physiologic mechanisms underlying their regulation remain poorly understood. It is not known for example if any of the surfactant proteins participate in the feedback regulation of phospholipids, other surfactant proteins, or their own synthesis. Two of the surfactant proteins SP-A, and SP-D are structurally similar to the serum mannose binding proteins and bovine conglutinin, both important host defense molecules. By analogy, SP-A and SP-D may be important in host defense. SP-D is the most recently described of the surfactant proteins. A high degree of sequence conservation among mammalian species supports an important role for this protein. In vitro evidence indicates that SP-D may regulate alveolar pool size. However, binding studies indicate that SP-D may recognize respiratory pathogens and thus facilitate host defense. SP-D is also expressed in gastric mucosa where it may have roles in the formation or regulation of a recently described oligolamellar phospholipid barrier to acid injury or as a host defense molecule. The purpose of this project is to study the regulation and function of the SP-D gene in rodents. The Specific Aims are: 1) to produce the transgenic mice carrying heterozygous and homozygous germ line null mutations to the SP-D gene; 2) to determine if a haploid SP-D gene dose results in a detectable alteration in SP-D expression; 3) to determine if alterations in SP-D gene expression lead to abnormalities in lung structure, surfactant component production, surfactant metabolism or function, or lung physiology; and 4) to determine if mice with homozygous or heterozygous SP-D deletions are more susceptible to bacterial or viral infections compared to otherwise syngeneic control animals. This research may clarify basic issues regarding the regulation of SP-D, its role in surfactant homeostasis, and its role as a host defense molecule.